Currently, there are a large number of methods and devices available to deliver intraspinal medications and the majority of them are based on continuous infusion by means of spinal catheters. Mostly the drugs for spinal delivery are anaesthetics. Presently two types of spinal anaesthesia techniques are routinely employed in surgical procedures. The two techniques are epidural and subarachnoid or intrathecal anaesthesia. With epidural anaesthesia, a catheter is usually placed in the spinal epidural space and the anaesthetics are administered through the catheter. U.S. Pat. No. 4,349,023 to Gross describes an example of such an epidural procedure. The advantage of this technique is that it allows for continuous administration over an extended period of time. There are however also disadvantages associated to this technique such as for instance, the non-uniform and often unpredictable distribution of the anaesthetics in the epidural space, which can be attributed to the characteristics of the epidural tissue, which is composed of fatty and fibrous material.
In contrast to the epidural space, the subarachnoid or intrathecal space is composed of a far more liquified and thus a faster, more uniform and more predictable distribution medium. Delivery of anaesthetics directly into the spinal subarachnoid space would therefore be preferable, were it not for one major side effect. The major problem is the severe post-operative headaches that often result from the puncture of the dural membrane (or dura) upon entrance of spinal catheters and needles into the subarachnoid space. Furthermore, the use of catheters and particularly small-bore catheters has been implicated in such complications as cauda equina syndrome, a neurological syndrome that is characterised by loss of sensation or mobility of the lower limbs. In May 1992, the FDA alerted Anaesthesia Care Providers to the serious hazard associated with continuous spinal anaesthesia by small bore catheters and has taken action to remove all small bore catheters from the market. An example of the intrathecal administration procedure is described in U.S. Pat. No. 4,518,383 to Evans.
The current method for intrathecal treatment of chronic pain is by means of an intrathecal pump, such as the SynchroMed. RTM Infusion System, a programmable, implanted pump available from Medtronic Inc., of Minneapolis, Minn. The system includes a catheter and a pump section. The pump section comprises a collapsible reservoir and a fill port for refilling the reservoir with fresh drug formulation. The system automatically delivers a controlled drug amount through the catheter by means of an electric peristaltic pump. The dosage, rate and timing can be externally programmed using radio waves. The SynchroMed.RTM Infusion System thus solves long-term delivery and dosage accuracy problems of other existing devices. At present the SynchroMed.RTM is used for spinal delivery of antinociceptive or antispasmodic therapeutics; because of the short half-life of these substances they require frequent readministration, and this is realized by the implanted pump. Although, the system has some major advantages over other existing methods, it also has some disadvantages. One disadvantage is the large, bulky size of the SynchroMed.RTM pump. Due to its size, the device must typically be implanted in the abdominal cavity of a patient and an extended catheter has to be passed through the patient's body to deliver the drug to the desired site of administration. In addition to problems with size and placement, the SynchroMed is burdened by complex electronics for both programming and pumping functionality. Furthermore, complications may arise as a result of the required surgical implantation and the possibility of leakage of the catheter as well as of the pump.
There is thus a need for an alternative spinal delivery method that reduces the risks associated with intrathecal drug delivery such as post-operative headache, meningitis, paralysis and even death by utilising the epidural delivery route. Further there is a need for a novel spinal delivery method that also reduces the surgical risks and disadvantages seen with implantable pump systems such as the SynchroMed.RTM Infusion System. The present invention discloses a method and apparatus that relates to controlled and enhanced epidural delivery of a biologically active agent.
The therapeutic efficacy of numerous highly effective biologically active agents (e.g. large compounds, hydrophilic and charged substances such as for example: proteins, (poly) peptides, and nucleotides) is limited, because they cannot or poorly penetrate the epidural space and other biological barriers, resulting in sub-therapeutic drug levels within the spinal structures and the brain. Distribution from the matrix of a polymeric implant or catheter of a spinal delivery device is based on passive diffusion, which is a slow process. During diffusion the compound (e.g. a peptide) may be subjected to substantial metabolism and clearance. As a result, the volume of tissue exposed to this compound is very small. Thus, due to the lipophilic nature of the epidural space, transport rate and migration distance of hydrophilic and/or ionised compounds within the epidural space is very low. In order to achieve therapeutic adequate levels substantially higher doses will be required in comparison to subarachnoid administration. Whereas subarachnoid administration is a more complicate surgical procedure accompanied with more risks such as post-operative headache, meningitis, paralysis and even death.
Therefore, there is also a large interest in development of a spinal drug delivery method that promotes fast and enhanced transport of therapeutic agents especially of large, hydrophilic and charged substances to the spinal structures and/or the brain (central nervous system, or CNS) for a long term period and that requires a minimum of surgical intervention and offers a minimum of side effects.
The present invention overcomes the disadvantages associated with existing implantable delivery methods such as, bulky reservoirs and/or pumps and the limited drug penetration depth by using phonophoresis or iontophoresis as a drug delivery enhancement technique. Iontophoresis has been defined as the active introduction of ionised molecules into tissues by means of an electric current. Iontophoresis devices require at least two electrodes, both being in electrical contact with some portion of a biological membrane surface of the body. One electrode commonly referred to as the “donor” or “active” electrode, is the electrode from which the biologically active agent, such as a drug or prodrug, is delivered into the body. Another electrode having an opposite polarity functions to complete the electric circuit between the body and the electrical power source. This electrode is commonly referred to as the “receptor” or “passive” electrode. During iontophoresis an electrical potential is applied over the electrodes, in order to create an electrical current to pass through the drug solution and the adjacent tissue.
Iontophoretic drug administration into body cavities by means of a catheter type of electrode has been first disclosed about 95 years ago. The Russians were in this field very productive and during the 1970's and 1980's a considerable number of patents were issued (e.g. SU Nos 532,890; 843,999; 1,005796). Recently, patents have been issued that disclose the treatment of blood-vessel related disorders (e.g. restenosis), bladder, uterus, urethra and prostate disorders.
U.S. Pat. Nos. 6,219,557; 5,588,961; 5,843016; 5,486,160; 5,222,936; 5,232,441; 5,401,239 and 5,728,068 disclose different types of iontophoresis catheters for insertion into hollow, tubular organs (bladder, urethra and prostate) or into blood vessels.
An implantable system for myocardial iontophoretic delivery of drugs to the heart is disclosed in U.S. Pat. No. 5,087,243.
Reference may be made to U.S. Pat. No. 5,807,306, which describes an iontophoresis catheter device for delivering a drug contained in a polymer matrix into internal tissue. The disclosed catheter may thus be an ideal tool for selective and controlled delivery to any body passageway or hollow organ. Because the drug is contained in a polymeric matrix, the risk of leakage typically associated with catheter devices is practically negligible. However, the disclosed device is not an implantable device and thus not suitable for long-term treatment. Further, the device requires manual operation.
The method of the present invention allows among other treatments also for an improved treatment of chronic pain by means of spinal delivery of anaesthetics or analgesic agents. At present there are no adequate objective measures of pain. The drug is being administered largely based on the sensation of pain expressed by the patient himself. It is however, not possible to measure the extent or amount of pain, whereas this may be of utmost importance for determining the correct drug dosage. It has been suggested that the autonomic nervous system (ANS) may provide information regarding the presence of pain, because the ANS responds in order to maintain homeostasis within the organism to any internal or external stimulus thus also to pain. At present, the assessment of ANS activity is largely focused on the cardiovascular system. Unfortunately, cardiovascular measures such as blood pressure, heart rate and heart rate variability are not reliable indicators for the presence of pain. Skin potentials have been shown to be indicative for the presence of pain. Skin potentials or the sympathetic skin response reflect sweat gland activity and these glands are innervated by sympathetic C-fibers. However, the skin potentials are also largely influenced by the subject's response to emotional stimuli. Thus any emotional stimuli other than pain will influence the measurement. Other disadvantages of skin potentials are the fact that they are unstable and not reproducible.
I have also discovered the presence of fast oscillating potentials within the skin recorded potentials These so-called “fast waves” could not be blocked with atropine meaning that they are not transmitted by M-cholinergic sympathetic nerve fibers such as those innervating the sweat glands. The inventor also discovered that the “fast waves” are not subject to habituation such as “normal” skin potentials do. It has been hypothesised that these “fast waves” reflect sympathetic activity of autonomic brain centres that are most likely not located in the limbic system and are therefore not influenced by the emotional status of the subject. The “fast waves” can be recorded from the skin as well as from any conductive internal body part. It is further suggested that a change in a “fast waves” signal may be used as a tool for pain detection, because they are of autonomic nervous system origin and contain relevant information concerning changes in the internal environment. The detection of such a change in the “fast waves” could thus provide an excellent objective measure for the presence of pain and it may even be detected before the subject has become aware of the pain.